Synergistic antimicrobial compositions employing certain n-(phenyl-carbamyl)amino-benzene sulfonyl flourides

ABSTRACT

An antifungal and antibacterial composition consisting essentially of a mixture of an N-(phenyl-carbamyl)-aminobenzene sulfonyl fluoride with 3,4&#39;&#39;5-tribromosalicylanilide, 3,4,4&#39;&#39;trichlorocarbanilide, hexachlorophene, or 2,4,4&#39;&#39;-trichloro-2&#39;&#39;hydroxydiphenyl ether.

United States SYNERGISTIC ANTIMICROBIAL COMPOSITIONS EMPLOYING CERTAINN-(PI-IENYL-CARBAMYL)AMINO-BENZENE SULFONYL FLOURIDES Ludwig KonradHuber, King of Prussia, Pa.

Assignee: Pennwalt Corporation, Philadelphia,

Filed: Mar. 1, 1973 Appl. No.: 337,047

[75] Inventor:

US. Cl 424/233, 424/65, 424/315, 424/341, 424/322, 424/347, 106/15 AF,117/138.5, 162/161, 252/106 Int. Cl A0ln 9/02 Field of Search 424/233,322, 315; 252/106, 107

11 3,856,952 Dec. 24, 1974 Primary Examiner-Vincent D. Turner Attorney,Agent, or Firm-Carl A. Hechmer, Jr.

[57] ABSTRACT An antifungal and antibacterial composition consistingessentially of a mixture of an N-(phenyl-carbamyl)- aminobenzenesulfonyl fluoride with 3 ,4 '5- tribromosalicylanilide, 3,4,4'-trichlorocarbanilide, hexachlorophene, or 2,4,4-trichloro-2hydroxydiphenyl ether.

7 Claims, N0 Drawings SYNERGISTIC ANTIMICROBIAL COMPOSITIONS EMPLOYINGCERTAIN N-(PHENYL-CARBAMYL)AMINO-BENZENE SULFONYL FLOURIDES Thisinvention relates to an antimicrobial composition which comprises anovel mixture of active agents. More particularly, this inventionconcerns a combination of an N-(phenyl-carbamyl)aminobenzene sulfonylfluoride with at least one compound selected from the group consistingof 3,4, -tribromosalicylanilide, 3,4,4-trichlorocarbanilide,hexachlorophene, and 2,4,- 4-trichloro-2-hydroxydiphenyl ether. Saidcombination, or mixture, of agents provides unusually good inhibition ofbacterial and fungal growth, and for purposes of brevity herein may bereferred to merely as an antimicrobial composition.

3,4, 5-Tribromosalicylanilide, 3,4,4'- trichlorocarbanilide,hexachlorophene, and 2,4,4- trichloro-2'-hydroxydiphenyl ether are wellknown antibacterial agents which are widely used in various commercialproducts such as deodorant soaps, detergents, cosmetic formulations,oral hygienic preparations, etc. Although these antibacterial agents arequite effective as such, they have various disadvantages which tend tolimit their uses. For instance, hexachlorophene is known to be quitetoxic, and tribromosalicylamide, though less toxic, can effect skinsensitization and, like trichlorocarbanilide, exhibits only a lowactivity against gram negative bacteria such as Escherichia coli. It istherefore not only for economic but also for health reasons that morepotent formulations of these antimicrobial agents are needed to reducetheir operable concentrations while maintaining or broadening theirantimicrobial potency.

In the copending application for patent of Ludwig K. Huber, Ser. No.270,348, filed July 10, 1972 now U.S. Pat. No. 3,743,675, is disclosed anew family of compounds useful as antimicrobial agents, i.e., N-

(phenylcarbamyl )-aminobenzene-sulfonyl fluorides having the generalformula SO2F fluoride,

2 commercial antimicrobial agents when used in combination, i.e., inadmixture, therewith. "Synergism" refers to the phenomenon that thepotency resulting from the combination of two or more discrete agents isgreater than the sum of potencies of the agents taken independently.Since minor amounts of either class of agent in the compositions of theinvention embodied herein produce a synergestic result in biologicaleffects, the weight ratio of the N-(phenyl-carbamyl)aminobenzenesulfonyl fluoride constituent to one or more of the compounds from classconsisting of 3,45- tribromosalicylanilide, 3,4,4-trichlorocarbanilide,hexachlorophene, and 2,4,4-trichloro-2'- hydroxydiphenyl ether can bevaried widely, for example, in the range of from about 10:] to 1:10 byweight, although the preferred weight ratio is in the range of 8:1 to1:8.

The compositions of the invention or carriers containing them for theirbactericidal and fungicidal effects can be included in and on clothing,plaster, ink, wallboard, paper, adhesives, body care products (e.g.,shampoos, toothpaste, and deodorants and antiperspirant products such assoaps, creams, sprays and the like), synthetic detergents, cutting oils,polymeric materials, embalming fluids, oil paints and latex paints,emulsion polishes for floor finishes, biocides for use in oil field,wood and lumber, etc., to prevent the attack of various bacterial,fungal and algal pests. Representative of the bacteria and fungi whichthe compositions inhibit are the following: Staphylococcus aureus,Escherichia coli, Xanthomonas pruni, Penicillium digitalum, Aspergillusniger, Pullularia pullulans, Rhizopus st0l0- nifer, and the like.

In the following representative and clarifying examples, a convenientand meaningful method of measuring the effectiveness of antibacterialcompositions known as the Agar Dilution method is employed,

using various amounts and ratios of the individual antibacterial agents.Briefly stated, the test consists in dissolving the biostat or biostatmixture in an appropriate solvent (usually acetone) to obtain a stocksolution ten times the highest concentration to be tested. This stocksolution is then diluted by mixing 3 ml. of the stock solution with 27ml. of sterile nutrient agar. From this test concentrate, the other testconcentrations are made by direct dilution (or some of the subsequentlower concentrations) with the required amounts of untreated agar. Thetest mixtures are then poured into Petri dishes to fill one half of thearea. The other half contains the untreated control agar. Both thetreated and untreated agar are then seeded with appropriaterepresentative test organisms by streaking across the plate. After anappropriate incubation time (one to several days), the plates areexamined for inhibition properties of the biastat against the testorganism.

In the following examples the resistant gram positive bacteriaStaphylococcus aureus (ATCC-6538) was used as a representative testorganism. The symbol TBS stands for 3,4'5-tribromosalicylanilide, TCCfor 3,4,4'-trichlorocarbanilide, HEX for hexachlorophene, THE for2,4,4'-trichloro-2'-hydroxydiphenyl ether, and DSF" forN-(3,4-dichlorophenylcarbamyl)sulfanilyl fluoride, i.e., having thestructure mixtures is in all cases smaller than 1, in agreement with theobserved synergism.

to those skilled in the art the superior antimicrobial activities of thesynergestic combinations of this invention. The synergism demonstratedby the compositions described above is shown further by calculating thesums of the ratios Q Q and Q, Q,,, in which Q, and 0,; are thequantities of material A and material B used in the mixtures of minimuminhibitory concentrations, and Q and 0,, are the minimum inhibitoryconcentrations of the pure materials A and B, respectively, which willproduce an end point. When the sum of this value is 1, the effect is thesame as the toxic effect of each of the components of the mixture andthere is no synergism; if, however, the sum of ratios is smaller than 1,synergism has occurred. This technique for determining synergism isdiscussed in more detail in the article by F. C. Kull et al., Mixturesof Quaternary Ammonium Compounds and Long-chain Fatty Acids asAntifungal Agents, Applied Microbiology 9, pp. 538-541 (1951), andfurther by Shema et al., in U.S. Pat. No. 3,647,703, Mar. 7, 1972. As isevident, according thereto, from the data in the following table, thesum of ratios calculated for the various biocidal Exp. No. Compositionsof Biocidc, wt. 71 Qu/Qu Q /Q and representative of theN-(phenyl-carbamy1)aminobenzene sulfon 1 fluorid 2 DSF TBS th f y 6 gdescnbed above and 3 75% DSF 25% TBS 0.82 m e a orementioned applicationSer. No. 270,348, 4 50% DSF+509P TBS 0.64 now US. Pat. No. 3,743,675. 525 F 75 T S 6 15% DSF 8571 TBS 0.68 The following legend 18 used in thetable summary of 9 DSF TQC 079 results set forth below. 10 75% DSF 25%TCC 0.80 Bacterial Growth ll l 0.86

' 14 7571 DSF 2571 HEX 0.62 0 No growth; i=Trace growth; 1 Partialgrowth; 15 50% DSF 5071 HEX 0.63 16 25% DSF 7571 HEX 0.65 2 Intermediategrowth, 3 Moderate growth, 4 19 75% DSF 25% THE (L77 Heavy growth. 15%DSF 85% THE 0.86

First Series Exp. Composition of Biocide Concentration (total) ofBiocide (p.p.m.) No. wt. 71 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.31.4

1 100% DSF t 0 0 2 85'72 DSF +15% TBS 0 0 O O 3 757: DSF TBS i 0 0 0 4DSF -1- 5071 TBS 0 0 0 5 2571 DSF 71TBS 0 0 0 6 15% DSF TBS i O 0 0 0 00 7 TBS 0 Second Series Exp. Concentration (total) of Biocide (p.p.m.)No. composition of Biocide 0.25 0.35 0.4 0 5 0.5 0.55

8 100% DSF 1 1 1' 0 0 0 9 857: DSF +15% TCC 1' i 0 0 0 0 10 75% DSF 25%TCC I i 0 0 0 0 11 1571 DSF 85% TCC i i 0 0 0 0 12 100% TCC 1 i i 0 0 00 Third Series Exp. Concentration (total) of Biocide (p.p.m.) No.Composition of Biocide 0.2 0.25 0.3 0.35 0.4 0.45 0.5 0.55

13 100% DSF i i i i 0 0 14 75% DSF 257: HEX i 0 0 0 0 15 50% DSF 5071HEX i i 0 0 0 0 16 257: DSF 75% HEX i 0 0 0 0 0 17 100% HEX 2 1 i i 0 00 Fourth Series Exp. Concentration (total) of Biocidc (p.p.m.) N0.Composition of Biocide 0.01 0.02 0.03 0.04 0.06 0.08 0.10 0.15 0.20 0.250.30

18 100% DSF 2 1 t 0 19 75% DSF 25% THE 1 i 0 0 0 0 20 15% DSF l- 85% THEi 0 0 0 0 21 100% THE 0 0 0 0 The foregoing results made demonstrablyapparent lclaim:

1. An antibacterial and antifungal composition consisting essentially ofan effective amount of a mixture of (A) an N-(phenyl-carbamyl)amino-benzene sulfonyl fluoride of the formula where X is chlorine,bromine, trifluoromethyl, methoxy or fluorosulfonyl; X is hydrogen,chlorine, bromine, trifluoromethyl, methoxy or fluorosulfonyl; m is awhole number from 1 to '3, and n is a whole number from 1 to 3, with (B)a compound selected from the group consisting of 3,4,5-tribromosa1icy1anilide, 3,4,4'-trich1orocarbani1ide, hexachlorophene,and 2,4,- 4-trichloro-2'-hydroxydiphenyl ether, there being in themixture 15 to 85% by weight of component (A) and, from 85 to 15% byweight of component (B).

2. The composition according to claim 1 wherein theN-(phenyl-carbamyl)aminobenzene sulfonyl fluoride is selected from thegroup consisting of 3. The composition according to claim 1 wherein theN-(phenylcarbamyl)aminobenzene sulfonyl fluoride isN-(3,4-dichlorophenylcarbamyl)-sulfanilyl fluoride.

4. The composition according to claim 1 wherein component (A) isN-(4-bromophenyl-carbamyl)- sulfanilyl fluoride.

5. The composition according to claim 1 wherein component (A) isN-(3-trifluoromethyl-4- chlorophenyl-carbamyl)-sulfanilyl fluoride.

6. The composition according to claim 4 wherein component (B) is 3,4,5-tribromosalicylanilide.

7. The composition according to claim 5 wherein component (B) is 3,4, 5tribromosalicylanilide.

l l l =l

1. AN ANTIBACTERIAL AND ANTIFUNGAL COMPOSITION CONSISTING ESSENTIALLY OFAN EFFECTIVE AMOUNT OF A MIXTURE OF (A) AN N(PHENYL-CARBAMYL)AMINO-BENZENE SULFONYL FLUORIDE OF THE FORMULA
 2. The compositionaccording to claim 1 wherein the N-(phenyl-carbamyl)aminobenzenesulfonyl fluoride is selected from the group consisting ofN-(3,4-dichlorophenyl-carbamyl)-sulfanilyl fluoride,N-(4-bromophenyl-carbamyl)-sulfanilyl fluoride,N-(3-trifluoromethyl-4-chlorophenyl-carbamyl)-sulfanilyl fluoride,N-(2,5-dichlorophenyl-carbamyl)-sulfanilyl fluoride,N-(3-fluorosulfonylphenyl-carbamyl)-sulfanilyl fluoride,N-(4-methoxyphenyl-carbamyl)-sulfanilyl fluoride, andN-(3,4-dichlorophenyl-carbamyl)-metanilyl fluoride.
 3. The compositionaccording to claim 1 wherein the N-(phenylcarbamyl)aminobenzene sulfonylfluoride is N-(3,4-dichlorophenylcarbamyl)-sulfanilyl fluoride.
 4. Thecomposition according to claim 1 wherein component (A) isN-(4-bromophenyl-carbamyl)-sulfanilyl fluoride.
 5. The compositionaccording to claim 1 wherein component (A) isN-(3-trifluoromethyl-4-chlorophenyl-carbamyl)-sulfanilyl fluoride. 6.The composition according to claim 4 wherein component (B) is 3,4'',5-tribromosalicylanilide.
 7. The composition according to claim 5wherein component (B) is 3,4'', 5-tribromosalicylanilide.